Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
  • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
  • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
  • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
  • C07D333/70—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems

Definitions

• the present invention relates to methods of making optically pure compounds that inhibit the enzyme glycinamide ribonucleotide formyl transferase (GARFT) .
• the invention also relates to the optically pure intermediates useful for making the optically pure GARFT-inhibiting compounds and to the syntheses of these intermediates.
• GARFT glycinamide ribonucleotide formyl transferase
• GARFT is a folate-dependent enzyme in the de novo purine biosynthesis pathway. This pathway is critical to cell division and proliferation. Shutting down this pathway is known to have an antiproliferative effect, in particular, an antitumor effect. Compounds that inhibit GARFT consequently inhibit the growth and proliferation of the cells of higher organisms or microorganisms such as bacteria, yeast and fungi.
• a number of folate analogs have been synthesized and studied for their ability to inhibit GARFT.
• a prototypical specific tight-binding inhibitor of GARFT 5,10-dideazatetrahydrofolic acid, has been reported to show antitumor activity. See F.M. Muggia, "Folate antimetabolites inhibitor to de novo purine synthesis,” New Dru ⁇ s, Concepts and Results in Cancer Chemotherapy. Kluwer Academic Publishers, Boston (1992), 65-87.
• Antifolates or antifoles are a subclass of antiproliferative antimetabolites and are antagonists of the vitamin folic acid.
• antifolates closely resemble the structure of folic acid and incorporate the characteristic P-benzoyl glutamate moiety of folic acid.
• the glutamate moiety of folic acid takes on a double negative charge at physiological pH.
• this compound and its analogs have an active energy-driven transport system to cross the cell membrane and exert a metabolic effect.
• an optically pure compound having one chiral center is one that consists primarily of one of the two possible enantiomers (i.e., is enantiomerically pure), and an optically pure compound having more than one chiral center is one that is diastereomerically pure.
• optical pure is intended to mean a compound which consists of at least a sufficient amount of a single enantiomer (or diastereomer in the case of plural chiral centers) to yield a compound having the desired pharmacological activity.
• optical pure is intended to mean a compound that consists of at least 90% of a single isomer (80% enantiomeric or diastereomeric excess), preferably at least 95% (90% e.e. or d.e.), more preferably at least 97.5% (95% e.e. or d.e.), and most preferably at least 99% (98% e.e. or d.e.).
• An object of the present invention is to develop methods for preparing in good yields GARFT-inhibiting, antiproliferative compounds in optically pure forms. More specifically, an object of the invention is to develop a method for synthesizing optically pure compounds of formula
• A is an oxygen, sulfur or selenium atom
• Ar is a substituted or unsubstituted five- or six-membered aromatic group
• R. and R are independently a hydrogen atom or a moiety that forms together with the attached CO, a readily hydrolyzable ester group
• Ar is a substituted or unsubstituted five- or six-membered aromatic group and B is either an amino acid linked through the amino portion to form an amide or a .-Cg alcohol linked through the alcohol portion to form an ester, under conditions suitable to form a compound of formula I that is optically pure.
• the diol compounds of formula VII and their enantiomers are optically pure intermediates useful for making the optically pure GARFT inhibitors and antiproliferative agents.
• Ar is a 5-membered aromatic group having a sulfur ring atom.
• a preferred amino acid for B is diethyl glutamate, and a preferred C- ⁇ -Cg alcohol for B is methanol or ethanol.
• a preferred intermediate is 5- (3 (S) -4-dihydroxy-butyl) -thiophene-2-carboxylic acid ethyl ester.
• step (a) the reaction is carried out in the presence of (i) a transition-metal catalyst containing one or more metals selected from palladium, copper and nickel, and (ii) a non-nucleophilic auxiliary base (iii) in a solvent in which at least one of the reactant compounds is at least partially soluble; in step (b) the reducing agent is hydrogen gas in the presence of a metal catalyst containing palladium or platinum; and in step (c) the acid is p-toluenesulfonic acid.monohydrate and the reaction is carried out in methanol or ethanol.
• the invention relates generally to a method of making optically pure forms of antiproliferative compounds capable of inhibiting GARFT of formula I and their pharmaceutically acceptable salts:
• A is an oxygen, sulfur or selenium atom
• Ar is a substituted or unsubstituted five- or six-membered aromatic group
• R. and R_ are independently a hydrogen atom or a moiety that forms together with the attached C0_ a readily hydrolyzable ester group.
• the carbon at position 6 shown in formula I is in either the pure R or the pure S configuration.
• R. and R are independently selected from hydrogen, C.-Cg alkyl, hydroxyalkyl, alkylaryl and arylalkyl. More preferably, R. and R, are each hydrogen or a C ⁇ -C-, alkyl.
• A is sulfur
• Ar is preferably a five-membered aromatic group that is either substituted or unsubstituted.
• suitable substituents for the substituted species of Ar include alkyl groups such as methyl, ethyl and propyl, substituted alkyl groups, such as trifluoromethyl, and halogens, such as bromo and chloro.
• Preferred compounds of formula I are those of the subgenus defined by formula II:
• A' is sulfur or selenium
• Y is oxygen or sulfur
• C and D are independently hydrogen or a substituted or unsubstituted .-C 8 alkyl group.
• R. and R are independently hydrogen or a moiety that forms together with the attached CO, a readily hydrolyzable ester group.
• the C6 (asymmetric) carbon is in either the pure R or the pure S configuration.
• R. and R are independently selected from hydrogen, C.-Cg alkyl, hydroxyalkyl, alkylaryl and arylalkyl. More preferably, these substituents are independently hydrogen or a C.-C, alkyl.
• A is preferably sulfur.
• Y is sulfur.
• C is hydrogen or methyl
• D is hydrogen or methyl.
• suitable substituents for the substituted species of C and D include alkyl groups such as methyl and ethyl.
• the compounds of formulae I and II in which R and R, are hydrogen are active antitumor and antiproliferative compounds.
• the compounds where R. and R, are each a moiety, preferably an ethyl group, that forms with the attached CO, a readily hydrolyzable ester group, are intermediates for forming the free glutamic acid forms of the compounds and can also be hydrolyzed in vivo and thus act as prodrugs.
• the pharmaceutically acceptable salts of the compounds of formulae I and II include, e.g., non-toxic metal salts, such as alkaline metal and alkaline earth metal salts, and substituted and unsubstituted ammonium salts of the glutamic acid compounds of the above formulae.
• exemplary salts include sodium, potassium, lithium, calcium, magnesium, and substituted and unsubstituted pyridinium salts.
• the invention relates to methods of making both chiral forms (C6 - asymmetric carbon atom) of compounds of formula I or II.
• C6 - asymmetric carbon atom chiral forms
• R optically pure C6
• X is a halogen (bromo, fluoro, chloro or iodo) , preferably bromo
• B is either an amino acid, preferably diethyl glutamate, linked through the amino portion to form an amide, or a C. 1-C6-. alcohol, preferably methyl or ethyl alcohol, linked through the alcohol portion to form an ester
• Ar is as defined in formula I.
• the compound of formula III may be prepared in accordance with methods known to the art, such as described in J. Am. Chem. Soc. , vol. Ill (1989), 7664-7665.
• the reaction of the compounds of formulae III and IV is preferably carried out in the presence of (i) a suitable transition-metal catalyst, preferably palladium, copper, nickel or a mixture of two or more of these metals, and (ii) a non-nucleophilic auxiliary base, preferably a substituted amine (e.g., triethylamine or diethylamine), (iii) in a solvent in which at least one of the reactant compounds is at least partially soluble.
• a suitable transition-metal catalyst preferably palladium, copper, nickel or a mixture of two or more of these metals
• a non-nucleophilic auxiliary base preferably a substituted amine (e.g., triethylamine or diethylamine)
• a solvent in which at least one of the reactant compounds is at least partially soluble.
• the compound of the formula VII is reacted with a sulfonylating agent, preferably p-toluenesulfonyl chloride or methanesulfonylchloride, in the presence of a non-nucleophilic base, preferably triethylamine or diisopropylethyl amine, to give an intermediate mono-sulfonylated compound.
• a nitrogen nucleophile preferably sodium azide
• the azide functionality of the compound of formula VIII is reduced under suitable conditions, preferably hydrogen gas in the presence of a metal catalyst, and subsequently protected with a suitable nitrogen-protecting group, preferably t-butoxycarbonyl, benzyloxycarbonyl or benzyl, to provide a compound of formula IX:
• R. and R-. are independently hydrogen or a suitable nitrogen-protecting group that is readily removed in the presence of another sensitive functionality.
• Preferred nitrogen-protecting groups for R. and R-. are t-butoxycarbonyl, benzyloxycarbonyl and benzyl.
• a and Ar are as defined in formula I; B is as defined in formula IV; R. and R ⁇ are as defined in formula IX; and Ac is an acyl group, preferably acetyl.
• the compound of formula IX is reacted with an acylating or sulfonylating agent, preferably methanesulfonyl chloride or p-toluenesulfonyl chloride, in the presence of a non- nucleophilic base, preferably triethylamine or diisopropylethylamine, in a suitable solvent in which at least one of the reactants is at least partially soluble, to obtain an activated hydroxy group.
• the activated hydroxy group is subsequently displaced with a suitable nucleophile, preferably a thioacid salt, more preferably potassium thioacetate, to obtain a compound of formula X.
• the compound of formula IX is conveniently converted to the compound of formula X using (i) triphenylphosphine, (ii) diethyl, diisopropyl or dimethyl azadicarboxylate, and (iii) an acidic nucleophile, preferably thioacetic acid, (iv) in a suitable solvent.
• a and Ar are as defined in formula I; B is as defined in formula IV; R4. and R5-. are as defined in formula IX;' and R6. is hydrogen or a moiety that forms together with the attached CO- a readily hydrolyzable ester group, preferably C.-C 8 alkyl, hydroxyalkyl, alkylaryl or aralkyl, more preferably a C.-C, alkyl.
• the compound of formula X is treated with a nucleophilic base, preferably potassium carbonate, sodium carbonate, sodium hydroxide or potassium hydroxide, in an alcoholic solvent, preferably methanol, ethanol or isopropanol, in the presence of an alkylating agent, preferably dimethyl or diethyl chloromalonate, to obtain a compound of formula XI.
• a nucleophilic base preferably potassium carbonate, sodium carbonate, sodium hydroxide or potassium hydroxide
• an alcoholic solvent preferably methanol, ethanol or isopropanol
• a and Ar are as defined in formula I
• B is as defined in formula IV
• R 4. and R5_ are as defined in formula IX.
• the compound of formula XII is then reacted with a reducing agent, preferably sodium borohydride, in an alcoholic solvent, preferably methanol or ethanol.
• a suitable alkylating agent preferably diethyl or dimethyl chloromalonate, in the presence of a non-nucleophilic base, preferably sodium or potassium carbonate, to obtain the compound of formula XI.
• the compound of the formula XI is then treated to remove either or both of the R. and R-. protecting groups.
• a protecting group is t-butoxycarbonyl
• the compound may be treated with trifluoroacetic acid and then neutralized to obtain a compound of the formula XIII:
• the compound of formula XIII is reacted with an alkylating agent, preferably trimethyl or triethyl oxonium tetrafluoroborate, in a suitable solvent, preferably dichloromethane, to form an intermediate lactim ether.
• an alkylating agent preferably trimethyl or triethyl oxonium tetrafluoroborate
• a suitable solvent preferably dichloromethane
• the intermediate lactim ether is then reacted with guanidine in an alcoholic solvent, preferably methanol, ethanol or isopropanol, to form a compound of formula XIV.
• an alcoholic solvent preferably methanol, ethanol or isopropanol
• the compound of the formula XIII can be converted to the compound of the formula XIV by reacting the compound of the formula XIII with a thiolating agent, preferably P 2 s ⁇ or ( 2 ' 4_D i- s (4-methoxyphenyl) -1,3-dithia- 2,4-diphosphetane-2,4-disulfide) , to form the thiolactam intermediate.
• a thiolating agent preferably P 2 s ⁇ or ( 2 ' 4_D i- s (4-methoxyphenyl) -1,3-dithia- 2,4-diphosphetane-2,4-disulfide)
• the ether is then alkylated with an alkylating agent, preferably methyl iodide or trimethyl or triethyl oxonium tetrafluoroborate, and then with guanidine in an alcoholic solvent, preferably methanol, ethanol or isopropanol, to obtain the compound of the formula XIV.
• an alkylating agent preferably methyl iodide or trimethyl or triethyl oxonium tetrafluoroborate
• guanidine in an alcoholic solvent, preferably methanol, ethanol or isopropanol
• the compound of the formula XIV may be hydrolyzed under basic conditions to form a compound of the formula XV:
• the compound of the formula XV can be peptide-coupled by means well known to those skilled in the art with a glutamic acid diester hydrochloride to form a diester of the formula XVI:
• This compound is the enantiomer of the compound of the formula III.
• the compound of the formula XVII is then used in a manner analogous to that described above employing the compound of the formula III and the remainder of the synthesis is as described above, yielding an enantiomer of the formula XVI.
• the second method to prepare the C6 (S) forms of the compounds of the formulae I and II employs the compound of formula VII.
• the compound of formula VII is reacted with a suitable protecting group, preferably a silylating agent, more preferably t-butyldimethylsilyl chloride, in the presence of a non- nucleophilic base, preferably triethylamine, in a suitable solvent, preferably dichloromethane, to obtain a compound of the formula XVIII:
• Ar is as defined in formula I
• B is as defined in formula IV
• R_ is as defined in formula XVIII
• R-. is an acyl or sulfonyl group, preferably methanesulfonyl.
• the compound of formula XIX is reacted with a reagent suitable to remove the protecting group R_ and form an alcohol.
• a reagent suitable to remove the protecting group R_ and form an alcohol is a preferred reagent is a fluoride salt, preferably tetrabutylammonium fluoride.
• the resulting alcohol is then treated with a strong non-nucleophilic base, preferably sodium or potassium hydride, to obtain a compound of formula XX:
• the compound of formula XX is reacted with a nitrogen- containing anion, preferably sodium azide, in the presence of a Lewis acid, preferably lithium or magnesium perchlorate, in a suitable solvent, preferably acetonitrile, to obtain a compound of formula XXI:
• the compound of formula XXI is the enantiomer of the compound of formula VIII.
• the compound of formula XXI is processed in a manner analogous to that described above for the compound of formula VIII to prepare the compounds of the formula I having the C6 (S) configuration.
• Exemplary compounds of the formula I made in accordance with the invention include: (2- (5- [2- (2-amino-4-oxo-4,6,7,8- tetrahydro-3H-pyrimido[5,4-6] [1,4]thiazin-6(R) -yl) -ethyl] - thiophene) -2-L-glutamic acid) diethyl ester; (2- (5- [2- (2-amino- 4-OXO-4,6,7,8-tetrahydro-3H-pyrimido[5,4-6] [1,4]thiazin-6(S) - yl) -ethyl] -thiophene) -2-L-glutamic acid) diethyl ester; 2- (5- [2- (2-amino-4-oxo-4,6;7,8-tetrahydro-3H-pyrimido[5,4- 6] [1,4]thiazin-6 (R) -yl) -ethyl
• the compounds of the formulae I and II and their salts are particularly useful in the treatment of mammalian hosts, such as human hosts, and in the treatment of avian hosts. These compounds produce any one or more of an antiproliferative, antibacterial, antiparasitic, antiviral, antipsoriatic, antiprotozoal, anticoccidial, antiinflammatory, immunosuppressive and antifungal effect. The compounds are especially useful in producing an antitumor effect in a vertebrate host harboring a tumor.
• the compounds of the formulae I and n, as well as their pharmaceutically acceptable salts may be incorporated into convenient dosage forms, such as capsules, tablets and injectable preparations.
• Such pharmaceutical preparations may be prepared following conventional techniques of the pharmaceutical chemist involving steps such as mixing, granulation and compressing when necessary for tablet forms, or mixing, filling and dissolving the ingredients as appropriate, to give the desired products for oral, parenteral, topical, intravaginal, intranasal, intrabronchial, intraocular, intraaural and rectal administration.
• Solid or liquid pharmaceutically acceptable carriers, diluents or excipients may be employed in the pharmaceutical compositions.
• Solid carriers include starch, lactose, calcium sulphate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid.
• Liquid carriers include syrup, peanut oil, olive oil, saline solution and water.
• the carrier or diluent may include any prolonged-release material, such as glyceryl monostearate or glyceryl distearate, alone or with wax.
• the preparation may be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid (e.g. solution) or a nonaqueous or aqueous liquid suspension.
• a dose of a composition contains at least an effective quantity of the active compound (i.e., a compound of the formula I or a pharmaceutically acceptable salt thereof) and preferably is made up of one or more pharmaceutical dosage units.
• An effective quantity is a quantity sufficient to inhibit the folate metabolic pathway and derive the beneficial effects therefrom, e.g., throug administration of one or more of the pharmaceutical dosage units.
• An exemplary daily dose for a vertebrate host contains an amount up to one gram of active compound per kilogram body weight of the host, preferably one-half of a gram, more preferably 100 milligrams, and even more preferably, about 50 milligrams or less, per kilogram of the host weight.
• the selected dose may be administered to a warmblooded animal or mammal, for example, a human patient in need of treatment mediated by folate metabolic pathway inhibition, by any known method of administrating the dose including: topically, for example, as an ointment or cream; orally; rectally, for example, as a suppository; parenterally by injection; or continuously by intravaginal, intranasal, intrabronchial, intraaural or intraocular infusion.
• the residue was recrystallized from Et,0:hexanes, yielding 49.90 g of the diol (3) .
• the mother liquors were flash-chromatographed on silica gel, eluting 30-100% EtOAc in CH,C1,. This yielded another 5.81 g of the diol (3) as a white, low-melting solid.
• the overall yield of the diol (3) was 55.71 g (98%) .
• the crude oil was purified by flash chromatography on 250 g of silica gel, eluting hexanes: EtOAc (1:1) to remove baseline-colored impurities.
• the yield was 39.77 g (109%) of the thioacetate (8) as a red oil, which was used in step (i) without further purification.
• An analytical sample was obtained by flash chromatography on silica gel, eluting hexanes:EtOAc (4:1), producing a colorless oil.
• a solution of sodium ethoxide was prepared by dissolving 0.845 g (36.75 mmol) of sodium metal in degassed absolute ethanol under argon. To this solution was added 3.63 g (38.00 mmol) of guanidine hydrochloride. After stirring for 15 minutes, a solution of 4.55 g (12.25 mmol) of the lactim ether (11) in degassed absolute EtOH was added, and the mixture was heated at reflux for 1 hour. The cooled reaction was neutralized with 0.5N HCl, diluted with EtOAc, and extracted repeatedly. The combined EtOAc layers were washed with saturated NaCl, dried (MgS0 4 ) , and concentrated under reduced pressure.
• GARFT GAR-transformylase
• N 10 -formyl-5,8-dideazafolate (FDDF), 50 mM HEPES-KOH (pH 7.5), and 50 mM KCl.
• the reaction was initiated with the addition of enzyme to a final concentration of 11 nM, followed by monitoring of the increase in absorbance at 294 nm at 20 ⁇ C ( ⁇ « ⁇ . ⁇ 18.9 mM -1 cm "1 ).
• the GARFT inhibition constant (K.) was determined from the dependence of the steady-state catalytic rate on the inhibitor and substrate concentration. The type of inhibition observed was determined to be competitive with respect to FDDF by the dependence of the apparent K. (K. ) on the concentration of
• the Michaelis constant for FDDF, K m was determined independently by the dependence of the catalytic rate on the FDDF concentration.
• compound (40) was prepared in 87% yield according to the general procedure described for compound (10) . (m.p. 72-73°C) .
• ester (43) was prepared in 92% yiel according to the general procedure described for compound (13). (m.p. 253°C, with decomp.)
• compound (48) was prepared in 89% yield according to the general procedure described for compound (3) .

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